Pre-filled syringes have emerged as one of the fastest-growing choices for unit dose medication as the pharmaceutical industry seeks new and more convenient drug delivery methods. It simplifies the processing of primary packaging, no need of washing machine and tunnel, as well as less overfill in pre-filled syringes (compared to vials), which is an important advantage, particularly with costly biopharmaceuticals. RTU (ready-to-use) packaging with reducing costs while simultaneously improving quality gains the increase in parenteral delivery. Pre-filled syringes and RTU (ready-to-use) packaging brings new opportunities and challenges to pharmaceutical companies. As well as pharmaceutical machinery manufacturers are dedicating to provide new and more flexible solutions.
High Degree of Automation
With the increasing degree of automation in pharmaceutical manufacturing process, the particulate and bacterial contamination due to manual operations by operators can be minimalized. Recently, the new aseptic syringe filling line has become “fully automatic”, which is regarded as standard requirement. (Figure 1). In addition, isolators are increasingly becoming significant in the pharmaceuticals industry and in the advancement of product quality, reduction in operating costs and in the enhancement of production It has become a trend to separate sterile areas from manufacturing background surroundings.
In Process control (IPC) is also an important factor to further improve the quality of the filling process. At present, more attention is being paid to checking the fill weight and detecting the presence of the stopper. In the future, the check of packaging materials before filling will be required. For example, check the cap ring seal, container closure integrity of syringes. Faulty syringes will be sorted out before the filling process, the loss of liquid drug is reduced subsequently.
Figure 1(Tofflon Combo filling line for filling and stoppering syringes, vials and cartridges）
Diversities of Filling and Stoppering Process
Pharmaceutical packaging plays a key role in ensuring the sterility and quality of a drug product. Primary packaging, owing to the fact that it is in direct contact with the drugs, is considered to be critical to the preservation of the product’s stability, efficacy and safety. The use of ready-to-use (RTU), or pre-sterilized container-closure systems have emerged as a promising alternative to conventional primary packaging, adding significant value to streamline pharmaceutical fill operations without cleaning and validating components in contact with the product, particularly for expensive biopharmaceuticals. In this regard, peristaltic pumps are widely recognized because of the non-contact characteristics with drugs. This also greatly increases the capacity of the machine, as no need for online cleaning or online sterilization (CIP/SIP), which is time-consuming process.
The need for personalized filling systems is increasing. For example, high-viscosity product filling, thick and low-viscosity product filling, small-dose and high-precision filling requirements. These personalized products also pose new challenges and requirements for the filling system. Vacuum filling systems such as pumps, plunger pumps, time pressure methods, etc. can show special advantages in these areas.
In the stoppering process, the stopper is completed by mechanical stoppering, that is, the stopper is sealed by a guide tube to seal the syringe. With the development of biotechnology coated rubber plugs become popular in the process of stoppering. But is not suitable for mechanical stoppering process. Vacuum stoppering technology is a good solution for it stoppering of coated rubber plugs.The coated rubber plugs are inserted by vacuum stoppering technology. Firstly, there creates a vacuum condition inside the syringe, and then a rubber stopper is inserted, which will be pushed into the syringe by the pressure difference (Figure 2). The stopper is inserted by vacuum stoppering technology as tight as possible, but the stopper cannot be placed as precisely as that by mechanical stoppering.
Figure 2（Vacuum filling and vacuum stoppering technology）
Rise of New Packaging Material
RTU syringes have gradually gained its popularity in the pharmaceutical industry. RTU prefilled syringe can be used for small batch production as well as high output filling line. RTU packaging are gradually shifting from niche products to attractive alternatives for pharmaceutical companies. Manufacturers of glass packaging (also plastics) are contributing to this change. For example, RTU nested vials, tray vials and nested cartridges are currently on the market.
The biggest difference between nested and tray syringes is that the tray syringe is suitable for bulk filling machines, while the nested vials can usually be used with machines for syringes processing, including prefilled syringe de-bagging and de-lidding, as well as compatible with nested vials. Due to different shape, material and structure of the packaging, there still may be some necessary adjustments. Addressing the variety of packaging in the future will pose challenges for both machinery manufacturers and pharmaceutical companies.
However, there is still no guideline for these alternatives. The fully automatic de-bagging machine can ensure that there is no personnel intervening with the de-bagging process and the external bag can be decontaminated by spray sterilization. Material transfer can be made in a restricted access barrier systems (RABS) or Isolator. In this regard, double-sterile outer bag packaging will be widely used.
High Precise Filling
The filing process in aseptic process is a critical, particularly for high value of biopharmaceutical drugs, a non-loss filling method is a priority. The latest filling technology can almost avoid product loss. A statistical or 100% IPC during the production can ensure that the accuracy of the liquid dosage in all containers
Expandable in the Future
Given that the more personalized products, the more flexible solutions have become increasingly important. In particular, clinical research needs to have the highest possible flexibility in a compact space. It is considerable that a combination of manual, semi-automatic and fully automatic processes and multi-types of packaging to formulate the project. In this case, the infeed can be manual or semi-automatic to obtain maximum flexibility to adapt to new packaging types, especially to cope with differences in external packaging, while filling is still fully automatic. In order to ensure that each work step can be adapted to the type of packaging in the future, it is recommended to use robots in order to achieve flexible transfer of packaging among different stations, and even filling. In addition, it is also considerable to reserve a station for future function expansion.
Figure 3 Robotic transport system for containers
Different pharmaceutical companies have different expectations for manufacturing systems or product line. But they are all committed to provide the best protection for the machine operators and the products. Therefore, new filling and stoppering machines are usually highly automated and equipped with RABS or Isolators. When they are used in combination with upstream machines (such as de-bagging and de-lidding machines, etc.) and downstream machines (such as de-nesting machines, inspecting machines, plunger rod insertion and labelling, etc.), the result is a complete production line(Figure 4), and In the future, not only prefilled syringes, but also other RTU packaging will be widely used in the complete production line.
Figure 4(Tofflon PFS complete line solution)
What Can Tofflon Provide for PFS
Tofflon provide solution for primary packaging solution of PFS and RTU nested packaging ,including de-bagging machine for removing the external bag of the tub and de-lidding machine for Tyvek removal; filling and stoppering machine is compatible with nested syringes, cartridges, vials for filling and sealing, de-nesting machine is for picking vials from the nest, capping machine for vials, etc. Customized filling systems for special products, vacuum filling and stoppering, nitrogen flushing, 100% weight check IPC, glass ball beading and CIP/SIP will be provided. Furthermore, the barrier systems of RABS, CRABS or Isolator can be integrated with as a whole system.